The treatment of cancer has thus far proved problematic. While xe2x80x9ccancersxe2x80x9d share many characteristics in common, each particular cancer has its own specific characteristics. Genetics and environmental factors have a complex interplay in severity and prognosis of treatment. Thus, treatment must be carefully tailored.
Certain pharmaceutical treatments have proved useful for one form of cancer, but not others (Hollad and Frei, et al, Cancer Medicine, 4th ed. Publisher Williams and Wilkens). Other treatments such as radiation, while partially useful for a range of cancers, do not typically result in a complete cure. Indeed, given the severity of many cancers and the mortality rate, a drug can be deemed successful if it improves quality of life, e.g., by delaying growth of tumors, or prolongs lifexe2x80x94without actually curing the condition. Thus, in many circumstances, an individual is treated with a compound or combination of treatments that can eliminate 90-95% of the malignant cells, but the remaining cells can regrow and metastasize, ultimately resulting in death. Among cancers with particularly poor ultimate prognoses is ovarian cancer.
Combination therapies, while desirable, are a hit or miss proposition. The treatments are typically not addictive. In many cases, cross effects and treatment load can result in lower effectiveness for the combinations, than either treatment alone. Problems encountered include multiple drug resistance (MDR), where the malignant cell in essence pumps the cytotoxic compounds and other compounds out of the cell, thereby preventing continued useful treatment of the cancer.
There are a number of cytotoxic agents that are currently being used or studied for the treatment of cancer. One of these, Paclitaxel, (also referred to as TAXOL(copyright)) was first identified in 1971 by Wani and collaborators (Wani MC et al., 1971 J. Am. Chem. Soc., 93: 2325-2327) following a screening program of plant extracts of the National Cancer Institute. This complex diterpene shows cytotoxic activity against several types of tumors and is presently used in the treatment of some cancers such as ovarian and breast cancers. Clinical studies suggest that TAXOL(copyright) could eventually be used in the treatment of over 70% of human cancers.
Paclitaxel differs from other cytotoxic drugs by its unique mechanism of action. It interferes with cell division by manipulating the molecular regulation of the cell cycle. Paclitaxel binds to tubulin, the major structural component of microtubules that are present in all eukaryotic cells. Unlike other antimitotic agents such as vinca alkaloids and colcichine, which inhibit the polymerization of tubulin, paclitaxel promotes this assembly of tubulin and stabilizes the resulting microtubules. This event leads to the interruption of cell division, and ultimately to cell death.
The antitumor property of taxoid compounds has also lead to the generation of new anticancer drugs derived from taxanes. Taxotere(trademark) (sold by Rhxc3x4ne-Poulenc Rorer), which is produced from 10-deacetylbaccatin III by hemisynthesis, is currently used in the treatment of ovarian and breast cancers.
While agents such as TAXOL(copyright) and Taxotere have made an advance in the treatment of metastatic ovarian and metastatic breast cancer, the majority of those treated still ultimately succumb to these diseases. xcex2-lapachone, a quinone, is derived from lapachol (a naphthoquinone) which can be isolated from the lapacho tree (Tabebuia avellanedae), a member of the catalpa family (Bignoniaceae). Like camptothecin and topotecan, xcex2-lapachone inhibits DNA Topoisomerase I (Li, C. J., et al., J. Biol. Chem., 1993). This compound has been found to be effective against several types of cancer cells in vitro, including lung, breast, colon and prostate cancers and malignant melanoma (Li, C. J., et al., Cancer Research 55:3712-3715 (1995) and unpublished data).
xcex2-lapachone works by disrupting DNA replication. Topoisomerase I is an enzyme that unwinds the DNA that makes up the chromosomes. The chromosomes must be unwound in order for the cell to use the genetic information to synthesize proteins; xcex2-lapachone keeps the chromosomes wound tight, and so the cell can""t make proteins. As a result, the cell stops growing. Because cancer cells are constantly replicating and circumvent many mechanisms that restrict replication, as is the case with normal cells, they are more vulnerable to topoisomerase inhibition than are normal cells. However, treatment with these compounds is also only partially successfulxe2x80x94inhibiting and delaying growth of the malignant cells.
No single drug or drug combination is curative for advanced metastatic. cancer and patients typically succumb to the cancers in several years. Thus, new drugs or combinations that can prolong onset of life-threatening tumors and/or improve quality of life by further reducing tumor-load are very. important.
We have surprisingly discovered that the administration of a compound that targets cells at G1 and/or S phase such as a topoisomerase I inhibitor such as xcex2-lapachone in combination with a compound that targets such cells at G2/M phase, e.g., a taxane derivative such as paclitaxel resulted in an unexpectedly greater than additive (i.e., synergistic) reduction in the number of tumors (and tumor volume in a mammal with metastatic tumors) as compared with the administration of these agents alone. Furthermore, the tumors did not grow back in several months of observation. In addition, no signs of toxicity or weight loss were observed in mammals so treated.
Accordingly, the present invention relates to a method for treating a mammalian tumor using a combination of a G2/M phase drug including, but not limited to, taxane, its derivatives and analogs, more preferably paclitaxel, and a G1 and/or S phase drug, preferably P-lapachone, or a derivative or analog thereof.
A list of two representative compounds is described in Table 1, infra. The combination of the present invention is particularly advantageous in the treatment of patients who have chemotherapeutically refractive metastatic cancer. The method of the present invention comprises administering to the mammal in combination an effective amount of a G1 and S phase drug, a G1 phase drug, a S phase drug, in combination with a G2/M drug. Preferably, the combination is (1) a topoisomerase I inhibitor such as xcex2-lapachone or its derivatives or analog thereof; and (2) taxane, its derivatives or analogs and pharmaceutically acceptable salts thereof.
As used herein, the phrase xe2x80x9ctaxane derivativexe2x80x9d means any taxane which is or may be used in cancer chemotherapy due to its antineoplastic properties. TAXOL(copyright) is a preferred taxane derivative.
As further used herein, the phrase xe2x80x9cxcex2-lapachonexe2x80x9d means lapachone (3,4-dihydro-s,3-dimethyl-2H-naphthol[1,3-b] pyran-5,6-clone) and derivatives and analogs thereof. Preferred derivatives and analogs are discussed below.